title: Switching addictions between HER2 and FGFR2 in HER2-positive breast tumor cells: FGFR2 as a potential target for salvage after lapatinib failure.
abstract: Agents that target HER2 have improved the prognosis of patients with HER2-amplified breast cancers. However, patients who initially respond to such targeted therapy eventually develop resistance to the treatment. We have established a line of lapatinib-resistant breast cancer cells (UACC812/LR) by chronic exposure of HER2-amplified and lapatinib-sensitive UACC812 cells to the drug. The mechanism by which UACC812/LR acquired resistance to lapatinib was explored using comprehensive gene hybridization. The FGFR2 gene in UACC812/LR was highly amplified, accompanied by overexpression of FGFR2 and reduced expression of HER2, and a cell proliferation assay showed that the IC(50) of PD173074, a small-molecule inhibitor of FGFR tyrosine kinase, was 10,000 times lower in UACC812/LR than in the parent cells. PD173074 decreased the phosphorylation of FGFR2 and substantially induced apoptosis in UACC812/LR, but not in the parent cells. FGFR2 appeared to be a pivotal molecule for the survival of UACC812/LR as they became independent of the HER2 pathway, suggesting that a switch of addiction from the HER2 to the FGFR2 pathway enabled cancer cells to become resistant to HER2-targeted therapy. The present study is the first to implicate FGFR in the development of resistance to lapatinib in cancer, and suggests that FGFR-targeted therapy might become a promising salvage strategy after lapatinib failure in patients with HER2-positive breast cancer.
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Azuma
authors.forename: Junji
authors.initials: J
authors.lastname: Tsurutani
authors.forename: Kazuko
authors.initials: K
authors.lastname: Sakai
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Kaneda
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Fujisaka
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takeda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Watatani
authors.forename: Tokuzo
authors.initials: T
authors.lastname: Arao
authors.forename: Taroh
authors.initials: T
authors.lastname: Satoh
authors.forename: Isamu
authors.initials: I
authors.lastname: Okamoto
authors.forename: Takayasu
authors.initials: T
authors.lastname: Kurata
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D005784:Gene Amplification; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D016879:Salvage Therapy / Q000379:methods*; D017211:Treatment Failure
chemical_list: D000970:Antineoplastic Agents; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2; C496353:FGFR2 protein, human